Tuesday, 30 April 2013

Iranians scientists could be left out in the cold

"Just received the following notification as an Editor of a Journal. What do you think? May be a way around this is to anonymise all journal reviews; i.e. the reviewer has not idea where the paper is coming from and who wrote it. Isn't science above politics? What about all the MSers in Iran; should we ignore them?"

US editors and reviewers can no longer handle submissions by authors employed by the Government

The Office of Foreign Assets Control (OFAC) of the US Department of the Treasury administers and enforces economic and trade sanctions. As a result of OFAC sanctions we have been made aware that US editors, US Elsevier staff and US reviewers are now unable to handle scientific manuscripts where any of the authors are employed by the Government of Iran. This includes the research departments of the various oil and gas companies which are deemed to be entities of the Government of Iran.

We realize that this OFAC regulation will cause some inconvenience in your role as an editor but Elsevier is legally obliged to ensure that all reasonable efforts are made to avoid submissions from Iranian government agencies and companies being handled by US editors, US Elsevier staff and US reviewers. Please be aware that editors, Elsevier staff and reviewers from outside the US may still handle these manuscripts and that this OFAC regulation does not pertain to manuscripts where the authors are based at Iranian academic and research institutes. Manuscripts originating from a clinical setting that are not government run, for example, a hospital or clinical practice are also exempt from this regulation.

To view the official OFAC regulation, please click here.

In practice the result of these sanctions will mean that:
  • Submissions where any author is based in Iran, and is not at an academic and research institution, cannot be handled by US-based editors, US Elsevier staff, US reviewers, or any US citizens based outside of the US.

  • If an Iranian author has dual affiliations (eg. university and government), their submission cannot be handled by US-based editors, US Elsevier staff, US reviewers, or any US citizens based outside of the US.

  • Affiliations of Iranian authors should therefore be checked, and any manuscripts which fall under this OFAC regulation delegated to a non-US editor, before handling.

  • When assigning reviewers, affiliations of Iranian authors should also be checked, and any papers which fall under this OFAC regulation should only be sent to non-US reviewers. (As an editor you should do what is reasonable to determine the nationality of a reviewer e.g. check their email address. This check does not extend to emailing reviewers directly to confirm their nationality or location). Unless there is specific knowledge that a non-US-based reviewer is a US citizen, editors can send such submissions to reviewers based outside the US.

  • If your journal workflow involves all submissions being handled by US-based Elsevier staff, they will reject these manuscripts outright before they reach you.

  • Should there be no suitably qualified editor or reviewer, please reject the manuscript outright.

When rejecting manuscripts which fall under this OFAC regulation please use the new EES Decision Term "Reject - OFAC Sanctions" and the following text:

"As a result of OFAC sanctions all editorial staff who are US-based/US nationals are unable to handle scientific manuscripts which are authored by Iranian scientists, employed by the Government of Iran. Based on this OFAC regulation we are unfortunately unable to handle your manuscript. We wish you success with your submission to another Journal."

We apologize for the inconvenience this may cause. If you do have any questions please contact your Publisher.

Access to fampridine in England

"As you are aware from the 1st April the NHS has put in place a new funding system that is now controlled by Commissioners. Commissioning bodies are led by General Practitioners or GPs. The Commissioning Board have just ruled on access to Fampridine for MSers with walking difficulty."

"The following are some YouTube videos of MSers who have responded to Fampridine."

"Until NICE give Fampridine a green light as being cost-effective for the NHS it is unlikely that Fampridine, or any other new drug for MSers, will be funded under the new system."

CoI: multiple

Regional Access to DMT

Thousands of MSers are not getting drugs or the care and support they need, according to a campaign launched this week by UK MS Society.


Reasons to Live in Northern Ireland. They have a Similar Demographic, in terms of proportions of MSers, to Scotland.

Rip-off prices for drugs set by 'profiteering' Big Pharma giants

In Yesterdays News we hear about how companies selling cancer drugs are profiteering

A group of more than 100 leading cancer physicians from around the world, including nine from the UK, accuse the drug industry of “profiteering” – making a profit by unethical methods such as by raising the cost of grain after a natural disaster.

The high prices mean the drugs may not be approved by the National Institute for Clinical Excellence in the UK forcing doctors to fill in a 14 page application apply to the Cancer Drugs fund for British patients who could benefit from them
In addition, the rising cost of existing drugs in a cash limited health service such as the NHS means treatment is denied to other patients with other conditions.

An example given is Glivec by Novartis. The cost of Glivec has risen from £18,000 (2001) per patient per year to around £21,000 in the UK, and from $30,000 to $92,000 in the US. This is despite the fact that all research costs were covered by the original price, and the number of patients treated and the length of time they are on the drug have both vastly increased because of the drug’s success.

The company thinks the cost is “high but worthwhile” and was estimated to yield annual revenues of $900 million, enough to cover its development cost in two years. A decade later Its annual revenues in 2012 were $4.7 billion (£3 billion). 


(Source Newspaper not verified details but the gist is all that is needed)

Glivec is a tyrosine kinase inhibitor and has been reported to have effects in EAE and possibly MS

Glaterimer acetate promotes remyelination

Rosato Siri MV, Badaracco ME, Pasquini JM.Glatiramer Promotes Oligodendroglial Cell Maturation In A Cuprizone-Induced Demyelination Model. Neurochem Int. 2013 Apr. doi:pii: S0197-0186(13)00131-9. 10.1016/j.neuint.2013.04.008. [Epub ahead of print]

The therapeutic potential of glatiramer acetate (GA) in Multiple Sclerosis has been apparent for many years and has been proven effective in Experimental Allergic Encephalomyelitis, one of its animal models. The cuprizone (CPZ) model for the CNS de/remyelination has gained a renewed interest during the past decade. CPZ-induced demyelination is considered to be primarily an oligodendrocyte loss with participation of the inflammatory response. As the blood brain barrier remains intact, we found this model advantageous for studying GA effects on CNS remyelination with minimum influence of the peripheral immune cellular component. Our results show that GA, given one week before the CPZ treatment, had a maturational effect functional to remyelination. However, myelin was unorganized as compared to controls. When GA was concomitantly injected with CPZ, oligodendroglial precursor proliferation diminished in favour of maturation and myelin recovered an organized disposition. GA-treated animals also show microglial cell (MG) activation. In vitro assays demonstrated that GA-primed MG cultures had a significant increase in IL-10 and IL-4 secretion. GA-challenged MG-conditioned media induced oligodendrocyte proliferation and subsequent differentiation. Our results suggest that, in addition to its well-recognized immunoregulatory properties, GA also has an effect on resident immuno-response, which leads mature oligodendrocytes towards CPZ-induced demyelination repair.

Mixture of Amino acids in Glaterimer Acetate

Yesterday we took some stick for asking what doesn't glaterimer acetate (GA) do? OK that was a bit tounge in cheek, but the reality is that the mechanism of immunomodulation attributed to GA has been very varied throughout the years. 

I suppose as it is doing something positive in MS who cares?

Well if you want to improve the effectiveness this would help. Some people think that a different mixture of amino acids is better, others scratch their heads.

I am interested to see that in this new study it is claimed that GA helps promote remyelination. I think this is yet more evidence for saying that mechanism of action could be varied. 

You suggested some explanations......I wonder how the remyelination would be due to cross linking Ig and causing TRegitopes

Cuprizone is a copper containing substance that is toxic to oligodendrocytes in certain bits of the brain, when added to the diet of rodents. Once removed then remyelination occurs. This may be speeded up by addition of chemicals that promote remyelination. This study suggests that copaxone can do this. The suggestion is that coxpaxone stimulates microglia to produce growth factors that stimulate oligodendrocytes to mature. Does this occur in humans? It would be good if it does. Does glaterimer acetate get into the brain? If if does not would this be important? If it does could it be important?

This study on remyelination repeats something done in a different remyelinating model some time ago,it is suggested to have other functions in neurodegenerative diseases too. 

It is hard to get you head round it.......not to say that you can't..and importantly we do not know how many drugs really work.

Psychosocial difficulties in MSers: predictors

What are the predictors for psychological and social predictors in MSers? No prizes for getting the correct answer. #MSBlog #MSResearch

Cieza et al. The psychosocial difficulties in brain disorders that explain short term changes in health outcomes. BMC Psychiatry. 2013 Mar 11;13(1):78.

BACKGROUND: This study identifies a set of psychosocial difficulties that are associated with short term changes in health outcomes across a heterogeneous set of brain disorders, neurological and psychiatric.

METHODS: Longitudinal observational study over approximately 12 weeks with three time points of assessment and 741 patients with depression, bipolar disorders, multiple sclerosis, parkinson's disease, migraine, traumatic brain injury and stroke. The data on disability was collected with the checklist of the International Classification of Functioning, Disability and Health. The selected health outcomes were the Short Form 36 and the World Health Organization Disability Assessment Schedule. Multilevel models for change were applied controlling for age, gender and disease severity.

RESULTS: The psychosocial difficulties that explain the variability and change over time of the selected health outcomes were energy and drive, sleep, and emotional functions, and a broad range of activities and participation domains, such as solving problems, conversation, areas of mobility and self-care, relationships, community life and recreation and leisure.

CONCLUSIONS: Our findings are of interest to researchers and clinicians for interventions and health systems planning as they show that in addition to difficulties that are diagnostic criteria of these disorders, there are other difficulties that explain small changes in health outcomes over short periods of time.

"Are you surprised that problems with (1) energy & drive, (2) sleep, (3) emotional functions,(4) problem solving, (5) conversation, (6) areas of mobility, (7) self-care, (8) relationships, (9) community life and (10) recreation & leisure may explain short term changes in health outcomes in MSers?"

"I note sleep has reared its ugly head again in this study. In my opinion, poor sleep is one of the biggest drivers of daytime fatigue and poor quality of life. If you have a sleep problem get it fixed."

"If you have not completed the following screening tool for sleep disorders please do. We are trying to assess how common sleep disorders are in the MSers who regularly read this blog. Once I get 120+ responses I will analyse the results. For those of you who don't want to participate in the survey you can simply download the questionnaire and assess yourself off line; I have loaded the questionnaire onto my slideshare site."

Monday, 29 April 2013

Postcode Lottery UK

Thousands of MSers are not getting drugs or the care and support they need, according to a campaign launched today by UK MS Society.


The MS Society wants equal access for all to treatment

A survey of more than 10,000 people with the condition found there were postcode variations, with people in Northern Ireland twice as likely as those in Wales to be taking drug therapy.

Six out of 10 eligible people with MS are not receiving "disease-modifying treatments.

Of those who were well-informed, saying they had sufficient information on treatments, 59% were taking disease-modifying treatments, compared with 27% of those who felt they did not know enough about them.



People who had access to a specialist MS neurologist or nurse were more likely to be on treatments.




In Europe, only Poland and Romania have a lower prescription rate for MS drugs than the UK compared to 27 European Countries.



These findings worryingly suggest that the likelihood of someone receiving a life-changing treatment is often based on luck – like where they live or how helpful their healthcare professional is – rather than their genuine clinical need,

The report also found that half of those who are struggling to make ends meet and need social care support are unable to access it.

• A quarter of people with MS who are of working age are employed, compared to three quarters of the wider UK population.

• Only 25 per cent of unemployed people with MS who want support to find paid employment are able to get it.

• Access to support to find, and hold on to, paid employment varies considerably across the UK. People in Scotland and Wales, who feel they need it, receive notably less support.

Those with a carer are 11 per cent more likely to need additional social care but are four per cent less likely to receive it.

Research:Manipulating the Cannabinoid System

EpubPryce G , A Cabranes, Fernández-Ruiz J, Bisogno T, Di Marzo T, Long JZ, Cravatt BF, Giovannoni G, Baker D. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors Mult Scler 1352458513485982, doi:10.1177/1352458513485982

Background: It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects. 

Objective: We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects. 

Methods: Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge. 

Results: Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184. 

Conclusions: This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use.

We showed that if you smoke pot then it has the potential to alleviate limb stiffness (spasticity). We also showed that this could get you "stoned". Importantly we showed that if you blocked the natural cannabis system , then we made things worse in beasties with spasticity from EAE. What this current study does is its shows that if you block the breakdown of the natural cannabis (you may have heard of endorphins these are the natural version of morphine in pain relief. Well anandamide is the natural version of cannabis) then it is good for controlling symptoms. The drugs work like SSRIs that block serotonin breakdown to treat depression, except that they blockbreakdown of the natural cannabis. Therefore, there is more around to treat symptoms, without causing the "high"

Whilst you can't get your hands on Sativex, we have been devising new ways so that you don't need to use a "drug of abuse"-honestly I never inhaled:-) . Pfizer the makers of the Pfizer riser (Viagra) have done a duff trial in the wrong sort of pain and have binned their drug. There are loads of other companies with drugs in this class ready to go. Sanofi (Genzyme) have about ten patents in this area.
COI. This work is from Team G, who are developing an alternative treatment for spasticity. This study is dedicated to Ana Cabranes a student from Madrid, Spain who spent a happy few months with the MDs  in London..who liked (favourite food) "soap" or was that "soup"..you had to be there..Unfortunately Ana lost her battle with Hodgkins Lymphoma.

Another action for glaterimer acetate

Høglund RA, Holmøy T, Harbo HF, Maghazachi AA. A One Year Follow-Up Study of Natural Killer and Dendritic Cells Activities in Multiple Sclerosis Patients Receiving Glatiramer Acetate (GA).
PLoS One. 2013 Apr 22;8(4):e62237. doi: 10.1371/journal.pone.0062237. Print 2013.

BACKGROUND:Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease. It is thought to be mediated by CD4(+) Th1/Th17 cells. More recently, cells of the innate immune system such as dendritic cells (DCs) and natural killer (NK) cells have been in focus. Glatiramer acetate (GA) is an approved drug for treating MS patients.
METHODOLOGY PRINCIPAL FINDINGS: In the current study we examined the activities of NK and DCs in nine relapsing remitting MS patients for up to one year after initiation of GA treatment. We observed that NK cells isolated from most of these patients have increased cytotoxic activity against K562 cells. Further analysis showed that the same NK cells lysed both autologous immature (i) and mature (m) DCs. In most patients this increased activity was correlated with increased NK cell activating cytotoxicity receptors such as NKp30, NKp44, NKp46 and NKG2D, and reduced expression of the inhibitory molecule CD158 on the surface of these NK cells. The expression of HLA-DR was increased on iDCs and mDCs in the majority of the patients, but no consistency was observed for the expression of HLA-I or HLA-E. Also, the co-stimulatory receptors CD80, CD83 or CD86 expression was down-regulated on iDCs and mDCs in most cases. Further, the expression of CCR6 was increased on mDCs at later time points of therapy (between 32-48 weeks).
CONCLUSIONS SIGNIFICANCE: Our results are the first showing the effects of GA treatment on NK cells in MS patients, which may impact future use of this and other drugs to treat this disease.
Yet another action of glaterimer acetate. It is affect the function of natural killer cells,is this important to the action of glaterimer acetate. These guys natural function is to fight infection and get rid of tumors... Dacluzimab affects NK function but is much more active at limiting relapse rate. What doesn't it do? Not much by the look of it so in another study
Sellner J, Koczi W, Harrer A, Oppermann K, Obregon-Castrillo E, Pilz G, Wipfler P, Afazel S, Haschke-Becher E, Trinka E, Kraus J.
Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis.
Clin Exp Immunol. 2013 Apr. doi: 10.1111/cei.12125. [Epub ahead of print]

An altered expression pattern of adhesion molecules (AM) on the surface of immune cells is a premise for their extravasation into the central nervous system (CNS) and the formation of acute brain lesions in multiple sclerosis (MS). We evaluated the impact of glatiramer acetate (GA) on cell-bound and soluble AM in the peripheral blood of patients with relapsing-remitting MS (RRMS). Fifteen patients treated de-novo with GA were studied on four occasions over a period of 12 months. Surface levels of ICAM-1, ICAM-3, LFA-1 and VLA-4 were assessed in T cells (CD3+CD8+, CD3+CD4+), B cells, natural killer (NK) cells, natural killer T cells (NKT) and monocytes by 5-colour flow cytometry. Soluble E-selectin, ICAM-1, ICAM-3, PECAM-1, P-selectin and VCAM-1 were determined with a fluorescent bead-based immunoassay. The pro-migratory pattern in RRMS was verified by comparison with healthy controls and was characterized by an up-regulation of LFA-1 (CD3+CD4+ T cells, B cells), VLA-4 (CD3+CD8+ T cells, NK cells), ICAM-1 (B cells) and ICAM-3 (NK cells). Effects of GA treatment were most pronounced after 6 months and included attenuated levels of LFA-1 (CD3+CD4+) and VLA-4 (CD3+CD4+, CD3+CD8+, NK, NKT, monocytes). Further effects included a lowering of ICAM-1 and ICAM-3 levels in almost all immune cell subsets. Soluble AM levels in RRMS did not differ from healthy controls and remained unaltered after GA treatment. The de-regulated pro-migratory expression profile of cell-bound AM is altered by GA treatment. While this alteration may contribute to the beneficial action of the drug, the prolonged development and unselective changes indicate more secondary immune regulatory phenomena related to these effects.

ICAM= adhesion molecule so is LFA-1 and VLA-4 (integrins) and the selectins some of them go down abit after treatment so they may not bind to antigen presenting cells as well as they could and maybe also may bind less to blood vessels in the brain. What else doesn't GA do?

MS Awareness Week 2013, UK Are you getting Loud?

This week is the MS Week (29 April – 5 May 2013) in UK, in USA it was in March 

This week the UK MS Society will be launching a report based on surveys of thousands of MSers. This gives a picture of access to MS treatments and services across the UK... sadly I think I can guess the content....I maybe will do a post once I get my hands on one.

Did you ask your MP to go to a reception in Westminster to get the report: "A lottery of treatment and care – MS services across the UK."

The MS Trust are looking for the SuperNurse, vote today (last Chance today to vote) for winner on 5 May 2013

There are lots more charties and other sites doing their big to raise awareness. What are you doing?

4-aminopyridine improves visual function

4AP or 4-aminopyridine helps MSers visual function. #MSBlog #MSResearch

"As you are aware MS often affects the optic nerves and may cause long standing visual dysfunction. Before getting to this studies results you need to understand about the tests we use to assess visual function."

"Visual acuity (VA) is what we measure using a wall chart; it simply tells us how good your vision is relative to normals. For example a visual acuity of 6/12 means that what you can see at 6m a normal person can see at 12m; in some parts of the world neurologists still use imperial charts that are in feet, i.e. 6/12 (meters) is 20/36 (feet)."

Visual acuity chart; this one is calibrated in feet.

"To assess how quickly the optic nerve conducts electrical impulses we use visual evoked potentials (VEPs). VEPs report several measures; with the P100 being the most common index used. The P100 stands for positive wave that occurs around 100 milliseconds in normal subjects. If you have had optic neuritis the P100 is delayed and you get a reading that is typically more than 108 milliseconds. If you have a drug that improves conduction velocity it will reduce the P100, i.e.improve conduction speed."

"OCT or optical coherence tomography is a relatively new way of assessing the retina or layers of nerves at the back of the eye. OCT uses light to measure the thickness of the nerve fibre layer. A typical attack of optic neuritis results in a loss of approximately 20% of the nerve fibres."

"This study shows that 4-aminopyridine or 4AP  improves visual function and conduction in eyes previously damaged by optic neuritis. 4AP is a drug that has been around for decades and was typically produced by compounding pharmacies, as it was never formally licensed for any indication. More recently it has been formulated as a slow-release formulation that is called fampridine. Fampridine has been licensed to improve walking speeds for MSers with walking difficulties. Once a drug becomes licensed it becomes illegal under EU law to continue formulating it therefore we can't prescribe 4AP in the EU, but only fampridine.  Fampridine costs a lot more than 4AP does and this has caused problems in many countries, notably The Netherlands and Switzerland. In these countries formulating pharmacies have apparently been threatened with legal action if they did not stop formulating the 4AP. This is an example of legislation that has been designed to protect innovators, by preventing other drugs or copies been made."

"This study, and others, has led to additional clinical trials in MSers with visual dysfunction post optic neuritis; some MSers are quite disabled by intermittent visual blurring as a result of temperature changes and fatigue. Watch this space."

Epub: Horton et al. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology. 2013.

OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled, crossover study was to examine if MSers with optic neuropathy would derive a therapeutic benefit from 4-aminopyridine (4-AP) treatment. Furthermore, the study was intended to determine if MSers with certain P100 latencies or retinal nerve fiber layer (RNFL) measures would be more likely to respond to therapy.

METHODS: MSers were enrolled in a randomized, placebo-controlled, double-blind, crossover study of 10 weeks duration. MSers underwent visual evoked potentials (VEP), optical coherence tomography (OCT), and visual acuity before starting 5 weeks of either placebo or 4-AP. After 5 weeks, they completed a second evaluation (VEP, OCT, and visual acuity) and were crossed over between treatment arms. Five weeks later, they had their final evaluation. All investigators were blinded to treatment arm until after data analysis.

RESULTS: On average, MSers had faster P100s on 4-AP when compared to placebo. A subset of MSers had distinct responses to 4-AP as measured by improvements in visual acuity. Finally, eyes with an RNFL measure between 60 and 80 µm had the highest response rate.

CONCLUSIONS: 4-Aminopyridine is useful for improving vision in MSers with demyelinating optic neuropathy. Future clinical trials may be able to enrich a MSer population for potential responders using OCT and VEP measures. Selecting MSers for future trials should use RNFL measures as part of inclusion/exclusion criteria.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence supporting the use of 4-AP in certain MSers with optic neuropathy to improve visual function (MSers with RNFL between 60 and 80 µm).

Clinical trial of Ampyra for Optic Neuritis in MS, ClinicalTrials.gov Identifier: NCT01337986

Sunday, 28 April 2013

Not all models of MS are in animals

Epub: Llobet et al. Stressed cybrids model demyelinated axons in multiple sclerosis. Metab Brain Dis. 2013 Apr 24.

Multiple sclerosis is likely caused by a complex interaction of multiple genes and environmental factors. The contribution of mitochondrial DNA genetic backgrounds has been frequently reported. To evaluate the effect of mitochondrial DNA haplogroups in the same genetic and environmental circumstances, we have built human transmitochondrial cell lines and simulated the effect of axon demyelination, one of the hallmarks of multiple sclerosis pathology, by altering the ionic gradients through the plasmalemma (membrane) and increasing ATP consumption. In this model, mitochondrial biogenesis is observed. This process is larger in Uk cybrids, which mirrors their lower oxidative phosphorylation capacity in basal conditions. This model replicates a process occurring in both MS patients suffering from multiple sclerosis and several animal models of axon demyelination. Therefore, it can be used to analyze the contribution of various mitochondrial DNA genotypes to multiple sclerosis. In this sense, a longer or stronger energy stress, such as that associated with demyelinated axons in multiple sclerosis, could make Uk individuals more susceptible to this pathology. Finally, pharmacologic compounds targeted to mitochondrial biogenesis could be a potential therapy for multiple sclerosis.

A cybrid (cytoplasmic hybrid) is a eukaryotic (Uk) cell (as opposed to prokaryotic found in bacteria) line produced by the fusion of a whole cell with a cytoplast. Cytoplasts are enucleated cells (cells minus a nucleus). This enucleation can be affected by simultaneous application of centrifugal force and treatment of the cell with an agent that disrupts the cytoskeleton. A cybrid is then a hybrid cell which combines the nuclear genome from one source with the mitochondrial genome from another source. Using this powerful tool, it is possible to dissociate the genetic contribution of the mitochondrial genome from that of the nuclear genome.

One problem associated with progression in MS is mitochondrial and energy problems. Could this be a new tool to study this and find new treatments to rectify the energy imbalance that occurs in cells during MS?

Research Viral-specific T cells augment autoimmmunity

EpubRainey-Barger EK, Blakely PK, Huber AK, Segal BM, Irani DN.Virus-induced CD8+ T cells accelerate the onset of experimental autoimmune encephalomyelitis: Implications for how viral infections might trigger multiple sclerosis exacerbations. J Neuroimmunol. 2013 Apr.

Viral infections can exacerbate multiple sclerosis (MS) through poorly defined mechanisms. We developed an experimental system whereby infection with an asymptomatic (no-symptoms) neurotropic (infects nerves preferentially) alphavirus caused a transient acceleration of experimental autoimmune encephalomyelitis (EAE) without altering the expansion or differentiation of autoreactive CD4+ T cells. Instead, this effect on the clinical course of EAE depended on CD8+ T cells that neither participate in viral clearance nor induce neuropathology in infected mice without EAE. Our system should be useful to further unravel how certain viral infections trigger MS exacerbations and to understand how CD8+ T cells can exert pathogenic effects within active demyelinating lesions.

Viral-specific T cells can augment myelin reactive immune responses.

Societal costs of MS

Why does MS have such a big impact on employment? #MSBlog #MSResearch

Kobelt et al. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2006 Aug;77(8):918-26.

OBJECTIVE: To assess overall resource consumption, work capacity and quality of life of MSers with MS in nine European countries.

METHODS: Information on resource consumption related to MS, informal care by relatives, productivity losses and overall quality of life (utility) was collected with a standardised pre-tested questionnaire from 13,186 MSers enrolled in national MS societies or followed up in neurology clinics. Information on disease included disease duration, self-assessed disease severity and relapses. Mean annual costs per patient (Euro, 2005) were estimated from the societal perspective.

RESULTS: The mean age ranged from 45.1 to 53.4 years, and all levels of disease severity were represented. Between 16% and 29% of MSers reported experiencing a relapse in the 3 months preceding data collection. The proportion of MSers in early retirement because of multiple sclerosis ranged from 33% to 45%. The use of direct medical resources (eg, hospitalisation, consultations and drugs) varied considerably across countries, whereas the use of non-medical resources (eg, walking sticks, wheel chairs, modifications to house and car) and services (eg, home care and transportation) was comparable. Informal care use was highly correlated with disease severity, but was further influenced by healthcare systems and family structure. All types of costs increased with worsening disease. The total mean annual costs per MSer (adjusted for gross domestic product purchasing power) were estimated at Euro 18,000 for mild disease (Expanded Disability Status Scale (EDSS) <4.0), Euro 36,500 for moderate disease (EDSS 4.0-6.5) and Euro 62,000 for severe disease (EDSS >7.0). Utility was similar across countries at around 0.70 for a patient with an EDSS of 2.0 and around 0.45 for a patient with an EDSS of 6.5. Intangible costs were estimated at around Euro 13,000 per patient.

The following graph has been taken from the paper to demonstrate the impact of disability on employment.

Figure legend: The proportion of patients employed or on long‐term sick leave is calculated as a percentage of patients aged 65 years. The reduced work capacity particularly at Expanded Disability Status Scale (EDSS) 2–3 compared with EDSS 4 is explained by an increased frequency of relapses in this group and hence a concentration of sick leave. 
"Are you surprised by these figures? I am aware that this is an old paper but it illustrates how devastating MS is on employment. Employment rates drop precipitously with increasing disability. At an EDSS 3.0, a level of disability that is not associated with loss of independence  close to 50% of MSers are unemployed. Why? I suspect this is driven by fatigue, depression, anxiety and cognitive impairment."

"If you have not done so already can you please take the time to compelet the employment survey below? We have had close to 100 respondents and would like to get over 100 before presenting the results to you. Thank you."

Saturday, 27 April 2013

Multiple Sclerosis Management 2013: A Changing Landscape

"I am speaking this afternoon at 'Multiple Sclerosis Management 2013: A Changing Landscape' meeting in Vienna. There are close to 400 neurologists at the meeting. The 'Changing Landscape'; refers to the emerging options that will be available to treat MS in the near future. I have to talk on 'Prospects for individualised therapy for MS'; I have decided to be controversial and make the case for MSer-choice and for the option of early aggressive-treatment. Many of you will recognise that as usual I have recycled my slides."

The meeting programme:

My presentation:

"I have a confession to make. After posting this morning on exercise and MS, and making the point about how good exercise is for your physical and mental well being I decide to skip the morning session and go for a run."

"My philosophy is that as a doctor you have to practice what you preach. The same applies for vitamin D supplementation; my family and I are all on 5,000U per day."

"I managed a slow 5 miles without too much pain; however, I did take 400mg of ibuprofen prophylactically. It is hard to believe that just a year ago I managed to run the London marathon. Despite the injury I feel a lot better for making the effort."


Epub: Radak et al. Percutaneous angioplasty of internal jugular and azygous veins in patients with chronic cerebrospinal venous insufficiency and multiple sclerosis: early and mid-term results. Phlebology. 2013 Apr.

Purpose: To assess the safety of endovascular treatment of chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis(MS).

Materials and Methods: A total of 72 patients with CCSVI and MS (44 with relapsing remitting - RR, 4 with primary progressive, 20 with secondary progressive and 4 with benign MS) underwent percutaneous angioplasty. Outcome measures were colour Doppler ultrasonography parameters, gradient pressure at the vein abnormality level, postoperative complications, re-stenosis, disease severity scored by means of Expanded Disability Status Scale (EDSS) and patients' assumption of disease status. Controls were done after one month on 72 patients, six months on 69 patients and one year on 61 patients, respectively (the average follow-up was 11 months).

Results: There were no post-operative complications. Colour Doppler ultrasonography showed significant improvement in cross-sectional area parameters (P < 0.05) and significant decrease in confluence velocity values (P < 0.05). Postoperative gradient pressure decreased, in internal jugular vein (IJV) significantly (P < 0.05). Re-stenosis appeared in 5.3% of patients. EDSS score was significantly improved (P < 0.01) and about half of patients reported significant or mild improvement in disease status and none of them worsening of symptoms.

Conclusion: Endovascular treatment of the IJV and azygous veins in patients with CCSVI and MS is a safe procedure with no post-procedural complications followed by significant improvement of IJV flow haemodynamic parameters and decrease in the EDSS score. Whether CCSVI percutaneous treatment might affect clinical improvement in patients suffering from MS is yet to be seen after completion of major multicentre clinical trials, still it seems like that this procedure is not negligible.

After last months negative reports an alternative view.

Epub: Simka et al. M Chronic cerebrospinal venous insufficiency is unlikely to be a direct trigger of multiple sclerosis. Mult Scler Rel Dis.

Background. Chronic cerebrospinal venous insufficiency, a vascular pathology affecting the veins draining the central nervous system can accompany multiple sclerosis and is suspected to be involved in its pathogenesis.

Objective. This study was aimed at exploring a potential role for chronic cerebrospinal venous insufficiency in triggering multiple sclerosis. If it were venous abnormalities responsible for neurological pathology, one should expect negative correlation, i.e. more severe vascular lesions in the patients with early onset of multiple sclerosis.

Methods. Localization and degree of venous blockages in 350 multiple sclerosis patients were assessed using catheter venography. Statistical analysis comprised evaluation of the correlations between severity of venous lesions and patients' age at onset of the disease.

Results. We found weak, yet statistically significant positive correlations between patients' age at onset of multiple sclerosis and accumulated and maximal scores of venous lesions. The patients, also those with duration of multiple sclerosis not longer than 5 years, who had their first attack of the disease at younger age, presented with less severe vascular lesions.

Conclusion. Positive correlation suggests that venous lesions are not directly triggering multiple sclerosis. There should be another factor that initiates pathological processes in the central nervous system.

Google trends: CCSVI continues to decline in interest as measured by Google's trend index

Research: Distinguishing NMO from MS

Storoni M, Davagnanam I, Radon M, Siddiqui A, Plant GT. Distinguishing Optic Neuritis in Neuromyelitis Optica Spectrum Disease From Multiple Sclerosis: A Novel Magnetic Resonance Imaging Scoring System. J Neuroophthalmol. 2013 Apr 19. [Epub ahead of print]

BACKGROUND:: The management of acute optic neuritis differs according to the underlying aetiology and techniques that may help with early differential diagnosis are therefore of considerable value.

OBJECTIVE:: We wanted to determine if multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) could be differentiated on the basis of neuroimaging abnormalities of the anterior visual pathways following an episode of optic neuritis.

METHODS:: Magnetic resonance imaging (MRI) findings of 27 patients diagnosed with MS (n = 15) or NMOSD (n = 12), who presented with acute isolated optic neuritis over a 3-year period, were reviewed retrospectively. The extent and location of inflammation along the anterior visual pathways were analyzed. A novel scoring system was devised, based upon the number of anatomical segments involved.

RESULTS:: Patients with NMOSD had a relative risk of 7.5 (confidence interval: 0.3-17.3) of having a score of 4 or more. Only NMOSD patients were found to have a score of 6 or higher. A trend for more posterior involvement of the anterior visual pathways was noted in the NMOSD group.

CONCLUSION:: This pilot study suggests that the MRI-based scoring system described here may aid in distinguishing patients with optic neuritis who have MS vs NMOSD. Visual pathway inflammation in NMOSD patients appears to be more extensive than in MS, mirroring the longitudinally extensive spinal cord lesions found in neuromyelitis optica.

NMO and MS may require different treatments.  People with NMO may have antibodies in their blood that help to distinguish whether the the optic nerve inflammation is due to MS or NMO. This study reports that MRI characteristics may help to spot NMO.

Research: change in physical activity

The impact of disability on your ability to exercise. #MSBlog #MSResearch

Epub: Motl et al. Longitudinal Change in Physical Activity and Its Correlates in Relapsing-Remitting Multiple Sclerosis. Phys Ther. 2013 Apr.

BACKGROUND: Physical activity is beneficial for MSers, but this population is largely inactive. There is minimal information on change in physical activity and its correlates for informing the development of behavioral interventions.

OBJECTIVE: This study examined change in physical activity and its symptomatic, social-cognitive, and ambulatory/disability correlates over a 2.5 year period of time in RRMSers.

METHODS: On 6 occasions each separated by six months, RRMSers (N = 269) completed assessments of symptoms, self-efficacy, walking impairment, disability, and physical activity. The participants further wore an accelerometer for 7 days.

RESULTS: There were significant linear changes in self-reported (p<.05) and objectively (p<.001) measured physical activity, self-efficacy (p<.05), walking impairment (p<.05), and disability (p<.001) over the 2.5 year period; there were no changes in fatigue (p=.70), depression (p=.80), and pain (p=.06). The changes in self-reported and objective physical activity were associated with change in self-efficacy (β=.49 & β=.61, respectively), after controlling for other variables and confounders.

CONCLUSION: Researchers and clinicians should consider designing interventions that target self-efficacy for the promotion and maintenance of physical activity in this population.

Stuart Rose: Running with Multiple Sclerosis

"It is not surprising that physical activity in MSers falls off with time. As MSers become more disabled it is increasingly hard for them to exercise. We need to develop better methods, tools and programmes to allow you to exercise. There is no doubt that exercise is a physical treatment and improves mental and physical well-being. As I write this I feel the need to go for a run. It is very depressing that I have a running injury and can't run very far or very quickly. I should be grateful that my injury should heal by itself in time. I wonder how MSers' feel when they realise that their disability is irreversible? I now understand why you are so desperate for effective neurorestorative therapies. Let's spread the hope; although neurorestoration is the holy grail of MS Research we need to continue working on it. Without research innovation dries up and hope fades." 

Teriflunomide for CIS

First oral treatment that is likely to get a license for CIS #MSBlog #MSResearch

Genzyme-Sanofi  announce positive results from the TOPIC trial for teriflunomide. The trial waCalendars designed to assess whether early initiation of teriflunomide in CISers can prevent or delay conversion to clinically definite multiple sclerosis (CDMS).

In the TOPIC trial, CISers received teriflunomide 14 mg and 7 mg were significantly less likely to develop CDMS, defined as occurrence of a second clinical attack, compared to placebo.

Primary results were: In CISers who received teriflunomide 14 mg, a 43 per cent reduction in risk of conversion to CDMS was observed over the two-year study period, compared to placebo (p=0.0087); In patients who received teriflunomide 7 mg, a 37 per cent reduction in risk of conversion to CDMS was observed over the two-year study period, compared to placebo (p=0.0271).

The average duration of teriflunomide exposure in TOPIC was approximately 16 months. Adverse events observed in the trial were consistent with previous clinical trials with teriflunomide in MS. The most common types of adverse events reported more frequently in the teriflunomide arms were ALT (Alanine transaminase) elevations, nasopharyngitis, headache, hair thinning, diarrhea and paresthesia. There were no deaths reported in either teriflunomide group over the course of the study. There was one death due to suicide in the placebo arm. The rate of treatment discontinuation due to adverse events was similar across treatment arms (9.1 per cent in placebo arm, compared to 12.1 per cent in 7 mg teriflunomide arm and 8.3 per cent in 14 mg teriflunomide arm).  

"These results are consistent with the phase 3 trials in RRMS and are not unexpected. They will make a difference if teriflunomide gets a license for CIS; a tablet will be more desirable than the injectable treatments."

Friday, 26 April 2013

I am a research scientist, and that's why I drink

It's not always easy being a Research Scientitst.
If you don't care..go to next post
If Interested Click here

Nature reducing their irreproducibility

#MSResearch  #EAE Time to improve your experiments

This is something that is well know that many things that are published in the top journals, turn out to be not quite right. 

Some people say over 50% of these papers may be crud.
Why is this the case?

(a) An honest error, where that was what the experimental result told you. If you aim to be first you don't know what is right, until people try to replicate it. If they can't it takes a load of studies to break the dogma created by the first study.

(b) You are racing to get the result before you are scooped, you do experiment that goes they way you want and that's QED-end of story, shame that it was the fluke that would turn out to be the odd one out.

(b) Liberal with the truth, you spin the story that ups the importance of the work to get that big hit.

(c) You don't know whats round the corner that will catch you out being liberal with the truth

(d) I am sure you can think of more ... and god forbid

(e) In a small fraction of cases it is made up.  
If your career depends on the right result would you make it up? You and the team need integrity.

Having just spent three years generating the tools to do the killer experiment that could give the Nature/Science paper (you hope) only to find it doesn't work the way you want. I can see the temptation.

(e) However, one thing that we have been banging on about is that the reporting of the experiments are so vague that no-one has a clue what was actually done so it is impossible to properly replicate the work. 

We showed that Nature was doing a bad job when it came to MS work and setting a bad example.

Therefore it is interesting that Nature have just issued reporting guidelines as part of the publishing process this no doubt will begin a change that we have been talking about. 

From next month, Nature and the Nature research journals will introduce editorial measures to address the problem by improving the consistency and quality of reporting in life-sciences articles. To ease the interpretation and improve the reliability of published results we will more systematically ensure that key methodological details are reported, and we will give more space to methods sections. We will examine statistics more closely and encourage authors to be transparent, for example by including their raw data.

Central to this initiative is a checklist intended to prompt authors to disclose technical and statistical information in their submissions, and to encourage referees to consider aspects important for research reproducibility (go.nature.com/oloeip).

Whilst this process will not remove crud, it will mean that the experimental design should be changed to avoid getting the cruddy results in the first place. However, it will be important that they monitor and implement this  

The neuroimmunology/EAE field need to embrace this because as we have shown people need to up their game.

Research: Myelin antibodies predicting MS

van Haren K et al. Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing– remitting multiple sclerosis Mult Scler 1352458513485653, first published on April 23, 2013 

EDSS is not responsive as an outcome measure

How long will the EDSS survive? #MSBlog #MSResearch

"This study confirms that the EDSS is not an ideal scale and that it is not responsive enough to change. This is why we are working on several other outcome measure projects to improve on the EDSS."

Epub: Rabadi & Vincent. Comparison of the Kurtkze Expanded Disability Status Scale and the Functional Independence Measure: measures of multiple sclerosis-related disability. Disabil Rehabil. 2013 Apr 19.

Background: MS is a disease which has a variable clinical presentation followed by a variable clinical course. Therefore, accuracy of clinical rating scales to measure disability at initial clinical presentation and during follow-up visits is essential to accurately capture the variability inherent in this disease. This is particularly vital when attempting to identify the efficacy of interventions.

Objective: This observational study in veterans with MS compared the Kurtkze Expanded Disability Status Scale (EDSS) and the Total Functional Independence Measure (TFIM) scale as measures of MS-related disability.

Methods: They retrospectively reviewed the electronic charts of 76 veterans with MS who were regularly followed in heir VA MS clinic. 

Results: The EDSS score accurately measured MS-related impairment at initial evaluation and follow-up relative to an Impairment Index. However, the EDSS score did not change over time, compared to the TFIM suggesting reduced sensitivity of the EDSS for detecting change in MS-related disability over time.

Conclusions: This suggests TFIM scale is a more sensitive measure of MS-related disability than EDSS for use in future MS clinical trials. 

Implications for Rehabilitation: This study highlights that given the paucity of scales to which EDSS has been compared, TFIM is a valuable adjunct to EDSS in measuring MS-related disability. TFIM is able to accurately measure the severity of MS-related disability and help provide for services MSers with MS-related disability would need. TFIM is an easy to administer and a sensitive scale to measure the change in MS-related disability following interventions.

Survey results: essential fatty acid nutriceutical survey

Most MSers responded that they are taking omega-3 fatty acid supplements, but not omega-6 #MSBlog #MSResearch

"The omega-3 fatty acids seem to be flavour of the day; I recall trying a particular brand that was derived from fish oil and it tasted terrible. I am told the newer generation supplements are not derived from fish oil and taste better. Despite the majority of you responding taking omega-3 fatty acids the evidence they work in MS is weak. Can I assume that you are convinced by the other health benefits of omega-3 fatty acids?"